Aging is a factor that exponentially increases the incidence of many diseases. Melatonin, a neuroendocrine agent, has been found to prevent the development or reverse some biochemical changes associated with brain aging. These changes include increases in oxidative and inflammatory events both of which are associated with senescence. The hypothesis underlying this application is that dietary melatonin may be of utility in retarding some of the undesirable aspects of brain aging. Arrest or reversal of trends associated with age will be evaluated by comparing patterns of mRNA and proteins from melatonin-treated mice with those from younger animals. Parallel studies using behavioral endpoints will reveal whether molecular changes detected, are reflected by altered cognition or motor strength. The degree of consonance between biological and behavioral changes may imply a causal relation. Changes in gene expression following treatment of aged mice with melatonin will be evaluated using array technology in combination with Northern blotting. Investigation of those genes associated with inflammatory or pro-oxidant events will be emphasized. The cytosolic pathways leading to genomic modulation will be sought. This will also involve the use of a cell line expressing melatonin receptors. Immunohistochemical identification of specific peptides from fixed tissue sections will allow a more precise localization of any changes in signaling pathways to be observed. Levels of proteins potentially affected by altered mRNA levels will be quantitated using ELISA and Western assays. The ability of melatonin to restore integrity of mitochondrial functioning and retard age-related mitochondrial DNA deletion will also be evaluated. The principal goal of this study is to contribute to the development of a rational nutritional strategy for delaying progression of brain aging.